Project Summary/Abstract Even with antiretroviral therapy, Human Immunodeficiency Virus (HIV)-infected individuals still have a greater mortality than uninfected individuals, mostly due to death from inflammation-related non-communicable diseases (NCD), such as cardiovascular disease (CVD) and kidney dysfunction. The drivers of this chronic immune activation and associated CVD remain largely unknown. Recent studies have shown that there might be significant HIV-associated disruptions in the gut microbial community, which is essential to human health and is involved in many metabolic and immune interactions. Our preliminary data from Sub-Saharan African populations, which bear a great burden of HIV and associated CVD, suggest that there are clear shifts in this microbial community and that these correspond to increased measures of systemic inflammation. Independent of HIV, changes in the gut microbial community have been shown to produce inflammatory metabolites that cause macrophage and platelet activation, thrombosis, and arterial plaque formation. We propose to study HIV-associated gut microbial changes in Sub-Saharan African populations and measure systemic immune activation and cardiovascular outcomes associated with these changes. We will then use in vitro and in vivo models to investigate the causative relationship between HIV-associated gut microbial community changes and CVD. To accomplish this goal, we will expose gut cell models to HIV-associated microbes of interest and measure the inflammatory response to these organisms. We will also transplant mouse models of atherosclerosis with stool microbial communities and then quantify the development of CVD induced by these communities. It is our hope that this work will identify mechanisms by which the gut microbial community might contribute to CVD pathogenesis in chronic HIV and provide opportunities for therapeutic interventions to extend lifespan and improve quality of life for HIV-infected individuals.